Antibody-drug conjugates are a kind of novel targeted therapeutic agents for the treatment of cancer and auto-immune diseases. The basic design philosophy originated from the notions of “magic bullet” and “drug targeting”, i.e. delivering drugs to the target region via specific carriers, which was firstly proposed by Paul Ehrlich in 1931. However, restricted by the technologies of antibody and high potency cytotoxic drug, the first ADC drug, Malotarg™ (for the treatment of acute myleocytic leukemia, AML), was not approved by FDA until 2000. Recently, FDA approved two ADC drugs, Adcetris™ (for the treatment of HL/ALCL by Seattle Genetics, 2011) and Kadcyla™ (for the treatment of breast cancer by Genentech, 2013), indicating that the rapid development stage of ADCs for cancer treatment is coming. In traditional ADC structures, highly-potent cytotoxic drugs are normally linked, via different linkers, to the ε-amino group of lysine residues or cysteine residues (after full/partial reduction of interchain disulfide bonds). The optimized DARs are preferred to be 2˜4. The large number of ε-amino groups of lysine residues (˜80/mAb) and the non-selective conjugation mode lead to the uncertainty of conjugation sites and conjugated drug numbers, and thus afford ADC product with high heterogeneity. For example, T-DM1 (average DAR˜3.5) has a DAR distribution ranging from 0 to 8 (Rapid Commun. Mass Spectrom. 2005, 19, 1806-1814). Similarly, when selecting cysteine residues as conjugation sites, although an antibody contains only four reducible inter-chain disulfide bonds, it must be partially reduced and conjugated to give ADCs with preferred average DAR (2˜4) (Bioconjugate Chem. 2005, 16, 1282-1290). As generally used reducing agents (DTT, TCEP, etc) couldn't selectively reduce the interchain disulfide bonds, the conjugation products thus obtained are not homogeneous either, containing multi-conjugates with DAR of 0, 2, 4, 6 and 8. Even for a fraction with specific DAR value, it is a mixture that contains conjugates with drugs conjugated at different sites. The heterogeneity of ADC products may ultimately lead to different PK, efficacy, and toxicity properties for different fractions. For example, fractions with higher DAR have, in some cases, been reported to clear more rapidly and contributed to more severe toxicity (Bioconjugate Chem. 2011, 22, 1994-2004).
To overcome the above mentioned shortcomings of traditional linker technologies, new linker technology is highly needed to provide site-specific conjugation products.